1. Field of the Invention
The present invention relates to biocompatible viscoelastic polymeric gel slurries, methods for their preparation, formulations containing them, and medical uses thereof.
2. The Prior Art
Hereinafter, the term "polymeric gel" is used to define a system which consists of at least two components, one being solvent and the other being polymer, which is not soluble in the solvent, and which exhibits no steady-state flow. The insolubility of the polymer is provided by, or results from crosslinking which may be due to chemical bonds or crystallites or some other kind of junction (J. D. Ferry, Viscoelastic properties of polymers. John Wiley & Sons, Inc., 1961, p. 391). The solvent component usually constitutes a predominant portion of the gel. When the solvent in a gel is water, such a gel is called a hydrogel. The most widespread practical use of a hydrogel is the use of collagen gels for tissue augmentation. In such instances, a hydrogel per se is not used; rather, it is used as a viscous solution injected into the dermal or subcutaneous tissue where the collagen immediately forms a gel and forms an artificial intercellular matrix (T. R. Knapp, et al, Injectable Collagen for Soft Tissue Augmentation. Plastic and Reconstructive Surgery, Vol. 60, 1977, pp. 398-405). Another use of a hydrogel is outside the body, on the surface of the eye as contact corneal lenses (M. F. Refojo, Ophthalmic Hydrogels, in Synthetic Biomedical Polymers, Ed. M. Szycher and W. J. Robinson, Technomics, 1980, p. 171). It has also been suggested to use hydrogels for drug delivery (B. E. McCarey, et al, Current Eye Research, Vol. 3, No. 8, 1984, p. 977), for wound treatment (P. Y. Wang, Infected Skin Wounds in Rodents, Polymeric Materials and Artificial Organs. Ed. C. G. Gebelin, ACS Symposium Series 256, ACS, Washington, D.C., 1984, p. 181). The noted applications of hydrogels are based on their three major properties: (1) the ability to hold large amounts of water, (2) to create and occupy space in the intercellular matrix, and (3) to form well defined solid shapes to refract light. However, there is another property which becomes extremely important when a hydrogel is used for augmentation of the intercellular matrix as for drug delivery, namely a high level of biocompatibility which is expressed as the absence of cytotoxicity and immunogenicity and the lack of causation of inflammation and foreign body reaction.
Recently, hydrogels with exceptionally good biocompatibility have been developed. These gels are based on hyaluronan (hyaluronic acid) crosslinked with vinyl sulfone (Balazs and Leshchiner, U.S. Pat. No. 4,605,691) or on cross-linked mixtures of hyaluronan with other polymers or low molecular weight substances (Balazs and Leshchiner, U.S. Pat. No. 4,582,865). Similar gels prepared from the chemically modified hyaluronan known as hylan are also described in the prior art (Balazs, et al, U.S. Pat. No. 4,713,448). These gels are used for drug delivery (Balazs and Leshchiner, U.S. Pat. No. 4,636,524) and other purposes in the medical field (E. A. Balazs and E. A. Leshchiner (1989). Hyaluronan, its crosslinked derivative--hylan--and their medical applications, In: Cellulosics Utilization: Research and Rewards in Cellulosics. Proceedings of the Nisshinbo International Conference on Cellulosics Utilization in the Near Future. (Eds. Inagaki, H. and Phillips, G. O.) Elsevier, Applied Science, New York pp. 233-241.